1-aryloxy-3-(substituted aminoalkylamino)-2-propanols

ABSTRACT

1-Aryloxy-3-(substituted aminoalkylamino)-2-propanols and pharmaceutically acceptable salts thereof have β-adrenergic blocking activity with some cardioselectivity and hence are useful as antihypertensive, antianginal, antiarrhythmic and cardioprotective agents and in the treatment of elevated intraocular pressure such as glaucoma.

SUMMARY OF THE INVENTION

This invention is concerned with novel compounds of structural formula:##STR1## and pharmaceutically acceptable salts thereof, wherein R¹, R²,R³, n and Y are as defined below, which have β-adrenergic blockingactivity with some cardioselectivity and hence useful asantihypertensive, antianginal, antiarrhythmic and cardioprotectiveagents, and in the treatment of elevated intraocular pressure such asglaucoma.

The invention is also concerned with processes for the preparation ofthe novel compounds; pharmaceutical formulations comprising one or moreof the novel compounds as active ingredient; and a method of treatinghypertension, arrhythmia, post myocardial infarction, angina andelevated intraocular pressure such as glaucoma by administration of anovel compound or pharmaceutical formulation thereof.

BACKGROUND OF THE INVENTION

A class of pharmaceutical agents known as β-adrenergic blocking agents,are available which affect cardiac, vascular and pulmonary functions andare mild antihypertensives. Specifically, these agents have thecapability of reducing heart rate, without counteracting vasodepressionor suppressing bronchodilation. β-adrenergic blocking agents, theirchemical structure and activity, are disclosed in "Clinical Pharmacologyand Therapeutics" 10, 292-306 (1969). Various β-adrenergic blockingagents are also described in the following U.S. Pat. Nos. 3,048,387;3,337,628; 3,655,663; 3,794,650; 3,832,470; 3,836,666; 3,850,945;3,850,946; 3,850,947; 3,852,291; 3,928,412; 4,134,983; 4,199,580;British Pat. No. 1,194,548; EP 42,592; and South African 74/1070.

Now, with the present invention there are provided novel β-blockingagents; processes for their synthesis, pharmaceutical formulationscomprising one or more of the novel compounds; and methods of treatmentwith the novel compounds or pharmaceutical compositons thereof whereinan antihypertensive, antianginal, antiarrhythmic, cardioprotective, orantiglaucoma agent is indicated.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention are represented by the formula I:##STR2## or a pharmaceutically acceptable salt thereof,

wherein: Y is (1) ##STR3## wherein m is 1 or 2, ##STR4## n is 1 to 8

R¹ is

(1) hydrogen,

(2) hydroxy, or

(3) hydroxymethyl;

R² and R³ are independently:

(1) hydrogen,

(2) halo such as chloro, bromo or fluoro,

(3) hydroxy,

(4) amino,

(5) di(C₁₋₅ alkyl)amino,

(6) mono(C₁₋₅ alkyl)amino,

(7) nitro,

(8) cyano,

(9) C₁₋₆ alkyl,

(10) C₃₋₈ cycloalkyl,

(11) C₂₋₅ alkenyl,

(12) C₁₋₄ alkoxy,

(13) C₁₋₄ alkylthio,

(14) C₂₋₅ alkenyloxy,

(15) C₁₋₅ alkanoyl, such as formyl,

pentanoyl or the like;

R⁴ and R⁵ are independently:

(1) hydrogen,

(2) C₁₋₆ alkyl, either unsubstituted or substituted with:

(a) hydroxy,

(b) C₁₋₄ alkoxy, or

(c) phenyl; ##STR5## wherein X is 0, 1 or 2;

R⁴ and R⁵ are joined together to form a 5 or 6 membered ring with thenitrogen to which they are attached, the 6-membered ring optionallyincluding another heteroatom selected from O, S and C₁₋₃ alkyl-N, suchas morpholino, N-methylpiperazino, pyrrolidino, or piperidino;

R⁶ is

(1) --CN,

(2) ##STR6## and

R⁷ is

(1) C₁₋₆ alkyl,

(2) C₁₋₄ alkoxy, or

(3) halo, such as chloro, bromo or fluoro,

In a preferred embodiment of the compound of this invention R¹ ishydrogen; R² and R³ are selected from hydrogen, halo, cyano, nitro andC₁₋₅ alkanoyl; n is 2, and Y is: ##STR7##

In an even more preferred embodiment, R¹ and R² are hydrogen, R³ iscyano, n is 2 and Y is as defined in the preferred embodiment.

The novel compounds of this invention include all the optical isomerforms as pure enantiomers or as mixtures containing the optical isomerssuch as racemic mixtures and compounds.

The compounds of the present invention also include the non-toxicpharmaceutically acceptable acid addition and quaternary ammonium salts.The acid addition salts are prepared by treating the compounds with anappropriate amount of a suitable organic or inorganic acid. Examples ofuseful organic acids are carboxylic acids such as maleic acid, tartaricacid, acetic acid, pamoic acid, oxalic acid, propionic acid, salicyclicacid, succinic acid, citric acid, malic acid, isethionic acid, and thelike. Useful inorganic acids are hydrohalo acids such as hydrochloric,hydrobromic, hydriodic, sulfuric, phosphoric acid, or the like.

Compounds of the present invention may be prepared by any convenientmethod, however, the preferred methods utilized will depend upon the R¹,R², R³, R⁴, R⁵ and Y groups and n. In the methods described below, theR¹ -R⁵ and Y groups and n are as defined above unless otherwiseindicated. Also, unless otherwise indicated, the starting materialsemployed are known in the literature, are commercially available, or canbe prepared by methods known to those skilled in the art. ##STR8##

For Method A, an epoxide I is reacted with a diamine of the type II in asuitable solvent such as methanol, ethanol, isopropanol, methylenechloride, THF or the like, at 0° C. to the reflux temperature of thesolvent for about 1-48 hours, preferably in isopropanol at 45° C. for 18hours, to yield III. Compound III can then be reacted with L-Y wherein Lis a leaving group such as ethoxy, chloro, bromo, methylthio, or thelike, and Y is as defined below, to yield IV. Examples of Y are:##STR9##

In Method B, the order in which the leaving groups are displaced isreversed. For example, amine III is reacted first with L-Q-L as definedabove, and then in a last step with amine VI to yield IVa. Theconditions utilized are the same as described in Method A. ##STR10##

For Method C, epoxide I is reacted with a diamine of the type VII toyield IV by the conditions described in Method A.

The β-adrenergic blocking properties of the novel compounds of thisinvention indicates that they are useful in the treatment of conditionssuch as hypertension, angina pectoris or certain arrhythmias which areknown to be amenable to treatment with β-adrenergic blocking agents.

For use as β-adrenergic blocking agents, the present compounds can beadministered orally, transdermally, or parenterally; i.e.,intravenously, interperitoneally, etc. and in any suitable dosage form.The compounds may be offered in a form (a) for oral administration;e.g., as tablets, in combination with other compounding ingredientscustomarily used such as talc, vegetable oils, polyols, benzyl alcohols,gums, gelatin, starches and other carriers; as liquids dissolved ordispersed or emulsified in a suitable liquid carrier; in capsulesencapsulated in a suitable encapsulating material; or (b) for parenteraladministration dissolved or dispersed in a suitable liquid carrier suchas solution or as an emulsion, or (c) as an aerosol or patch fortransdermal administration. The ratio of active compound to compoundingingredients; i.e., carrier, diluent, etc., will vary as the dosage formrequires. Generally, doses of the present compounds of from about 0.01to about 50 mg/kg and preferably from about 0.1 to about 20 mg/kg ofbody weight per day may be used. Dosage may be single or multipledepending on the daily total required and the unit dosage.

EXAMPLE 13-Methylamino-4[[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]ethyl]amino]-1,2,5-thiadiazole-1-oxidehemihydrate, (4) ##STR11##

To 1 (1.76 g, 7.5 mmole) in 2-propanol (10 ml) the diethoxythiadiazoleoxide, 2, in 2-propanol (20 ml) was added. The mixture was stirred atroom temperature for 1 hour then CH₃ NH₂ was bubbled through thesolution for 1 hour. The solvent was removed in vacuo and the residuewas purified on silica gel 60 by eluting with CHCl₃ -CH₃ OH-H₂ O(70-30-3 v:v:v) to yield 1.82 g (63.9%) of product 4. Analysissatisfactory for C₁₅ H₂₀ N₆ O₃ S.1/2H₂ O

EXAMPLE 23-Amino-4-[[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]ethyl]amino]-1,2,5-thiadiazole-1-oxide(0.25 CHCl₃

Following the same procedure as in Example 1, the title compound wasobtained by using ammonia instead of methylamine (64% yield). Analysissatisfactory for C₁₄ H₁₈ N₆ O₃ S.1/4CHCl₃.

EXAMPLE 3N-Cyano-N'-[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]ethyl]-N"-methylguanidine,(8) ##STR12## Step A: Preparation ofN-(2-Aminoethyl)-N'-cyano-N"-methylguanidine

Methylamine (1.58 g, 50.9 mmole) was condensed into 20 ml of 2-propanol.To this solution, (CH₃ S)₂ C=NCN (7.44 g, 50.9 mmole) in 2-propanol (40ml) was added (slight exotherm). The mixture was stirred for 15 minutesand then added dropwise over 15 minutes to 68.2 ml (1.02M) ofethylenediamine while stirring vigorously.

After 31/2 hours the solvent and the excess ethylenediamine were removedin vacuo. The residue was evaporated to dryness in vacuo twice with 100ml of 2-propanol then washed with ether (4×50 ml) and dried in vacuo toyield 7.0 g (97.4%) of 9.

Employing the procedure substantially as described in Example 3, Step A,but substituting dimethylamine for monomethylamine used therein, thereis produced N-(2-aminoethyl)-N'-cyano-N"-dimethylguanidine.

Step B: Preparation ofN-Cyano-N'-[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]ethyl]-N"-methylguanidine,(8)

The amine 6 (2.12 g, 15 mmole) in 2-propanol (30 ml) was heated to 40°C. and then the epoxide 7 (2.63 g, 15 mmole) in a mixture of 2-propanol(20 ml) and toluene (10 ml) was added dropwise to this solution. Thereaction mixture was stirred at 40° C. for 6 hours. The solvent wasremoved in vacuo and the product was purified on a silica gel columnusing CHCl₃ -CH₃ OH-H₂ O (70-30-3 v:v:v) as the eluent to yield 2.75 g(58%) of product 8; m.p. 128°-130° C. Analysis satisfactory for C₁₅ H₂₀N₆ O₂.1/4H₂ O.

EXAMPLE 4N-Cyano-N'-[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]ethyl-N",N"-dimethylguanidine

Following the same procedure as in Example 3, Step B, the title compoundwas obtained in 4.5% yield by usingN-(2-aminoethyl)-N'-cyano-N"-dimethylguanidine in place ofN-(2-aminoethyl)-N'-cyano-N"-methylguanidine.

EXAMPLE 5[[2-[[3-(2-Cyanophenoxy)-2-hydroxypropyl]amino]ethyl]-amino](methylamino)methyleneurea, (10) ##STR13## Step A: Preparation ofN'-carbamoyl-S,N"-dimethylisothiourea, (9)

(CH₃ NH) (CH₃ S)C=NCN, 5, (3.23 g, 25 mmole) was dissolved in a mixtureof H₂ O (50 ml) and concentrated HCl (100 ml) and stirred overnight atroom temperature. Another 50 ml concentrated HCl was added to thesuspension and the mixture was stirred at room temperature for anadditional 2 days. The aqueous solution was extracted with CHCl₃ (2×100ml) and evaporated to dryness in vacuo to yield 4.4 g (95.6%) of 9.

Step B: Preparation of[[2-[[3-(2-cyanophenoxy-2-hydroxypropyl]amino]ethyl]amino](methylamino)-methyleneurea dihydrochloride, (10)

Compounds 1 (2.35 g, 10 mmole) and 9 (1.83 g, 10 mmole) were dissolvedin 2-propanol (25 ml) and stirred overnight at room temperature. Thesolvent was removed in vacuo and the product purified on a silica gel 60column using CH₂ Cl₂ -CH₃ OH-H₂ O (80-20-2 v:v:v) as the eluent to yield0.9 g (24.3%) of product 10; m.p. 170° C. (dec.). Analysis satisfactoryfor C₁₅ H₂₂ N₆ O₃.2HCl.11/2H₂ O.

EXAMPLE 6N-[Cyanoimino-[[2-[[3-(2-cyanophenoxy)-2-hydroxypropyl]amino]ethyl]amino]]methylmorpholine,(11) ##STR14##

(CH₃ S)₂ C=NCN (2.19 g, 15 mmole) and morpholine (1.30 g, 15 mmole) weredissolved in 2-propanol (15 ml) and stirred at room temperature for 1hour. The reaction mixture was diluted with 2-propanol (15 ml), heatedto 45° C. and then 1 (3.53 g, 15 mmole) in 2-propanol (15 ml) was added.The reaction mixture was stirred overnight at 45° C., the solvent wasremoved in vacuo and the product purified on silica gel 60 using CH₂ Cl₂-CH₃ OH-H₂ O (80-20-2 v:v:v) as the eluent. Crystallization from CH₃ CNyielded 3.05 g of impure product which was rechromatographed on silicagel 60 using CHCl₃ -CH₃ OH-H₂ O (90-10-1 v:v:v) as the eluent.Crystallization from CH₃ CN-ether yielded 1.6 g (28.7%) of product 11.Analysis satisfactory for C₁₈ H₂₄ N₆ O₃.

EXAMPLE 7N-Cyano-N'-[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]ethyl]-N"-phenylguanidine

Following the same procedure as in Example 6, the title compound wasobtained by using aniline in place of morpholine. The title compound waspurified by chromatography on silica gel 60 by elution with CHCl₃ -CH₃OH-H₂ O (80-20-2 v:v:v); m.p. 146°-147° C. Analysis satisfactory for C₂₀H₂₂ N₆ O₂.

EXAMPLE 8N-2-[(3-(2-Cyanophenoxy)-2-hydroxypropyl)amino]-ethyl-N'-phenylthiourea##STR15## Step A: Preparation of N-(2-Aminoethyl)-N'-phenylthiourea,(12)

Compound 12 was prepared in 24% yield according to the procedure of O.Stoutland et al. [J. Org. Chem., (1959), 24 818] m.p., 131°-132°: (lit.,136°-137° C.).

Step B: Preparation ofN-2-[(3-(2-cyanophenoxy)-2-hydroxypropyl)amino]ethyl-N'-phenylthioureahydrate, (13)

A solution was prepared of 1.75 g (0.01 mole) of2,3-epoxy-1-(2-cyanophenoxy)propane, 7, in 50 ml of isopropyl alcohol,assisted by gentle warming and sonication. To this was next added 2.95 g(0.01 mole) of 12 all at once. The solution was refluxed for one hourthen stirred overnight at room temperature. The solution wasconcentrated in vacuo to 5.6 of gum, which was chromatographed over 150g of silica gel using 10% CH₃ OH/CHCl₃ (saturated with NH₃) and taking10 ml fractions. Fractions 12-41 gave 1.8 g of a foam which was found tobe nonhomogeneous. This material was rechromatographed over 200 g ofsilica gel using the same solvent system as before and taking 10 mlcuts. Fractions 12-30 gave 400 mg (12%) of yellow sticky 13, m.p.41°-47° C. R_(f) =0.64 (silica gel GF, 10% CH.sub. 3 OH/CHCl₃ (NH₃)).Mass spectrum, m/e 370 (M+); liquid chromatography showed 98% pure.Analysis satisfactory for C₁₉ H₂₂ N₄ O₂ S.1.6H₂ O.

EXAMPLE 9N-2-[(3-(2-Cyanophenoxy)-2-hydroxypropyl)amino]ethyl-N'-(3,5-dimethoxyphenyl)thiourea0.6 hydrate, (15) ##STR16## Step A: Preparation ofN-(2-Aminoethyl)-N'(3,5-dimethoxyphenyl)thiourea, (14)

A slurry of 9.75 g (0.05 mole) of 3,5-dimethoxyphenyl isothiocyanate in27 ml of ether was added dropwise to a stirred solution of 3.0 g (0.05mole) of ethylenediamine at room temperature. A five-degree rise intemperature was noted at the start of the one hour addition period. Asolid appeared during the addition, and stirring was continued for 2.5hours. The batch was allowed to stand overnight, and 100 ml of H₂ O wasadded. The solid was removed by filtration and the filtrate acidifiedwith 4.5 ml of concentrated HCl and evaporated to dryness on the steambath. The residue was sonicated with 100 ml of water and warmed to 50°C. for 10 minutes. This was filtered and basified to pH 10 with 10%NaOH. This gave 2.6 g of 14, m.p. 125°-126° C. Analysis satisfactory forC₁₁ H₁₇ N₃ O₂ S.

Step B: Preparation ofN-2-[(3-(2-cyanophenoxy)-2-hydroxypropyl)amino]ethyl-N'-(3,5-dimethoxyphenyl)thiourea,(15)

A solution of 1.28 g (7.3 mmoles) of2,3-epoxy-1-(2-cyanophenoxy)propane, 7, in 30 ml of isopropyl alcohol(warmed and sonicated) was treated with 1.86 g (7.3 mmoles) of 14 all atonce. This was heated under reflux for 2 hours and stirred overnight atroom temperature. After this, a small amount of solid (860 mg) wasremoved and the solution was concentrated to 2.3 g of semi-solid gum.This was chromatographed over 150 g of silica gel 60 using 10% (v/v) CH₃OH/CHCl₃ saturated with NH₃. Three fractions of 150 ml each were takenafter an 800-ml forerun. The third fraction provided 1.31 g of a whitefoam. This was chromatographed again, taking 10-ml fractions. Cuts 17,18 and 19 provided 80 mg (2.5%) of 15, m.p., 45°-55° C. Mass spectrum,m/e 430 (M+), base peak, m/e 195. Liquid chromatography showed 93.6%purity.

Analysis satisfactory for C₂₁ H₂₆ N₄ O₄ S.0.6H₂ O.

EXAMPLE 103-Amino-5-(2-{3-[(2-cyanophenoxy)-2-hydroxypropyl]-amino}ethylamino)-1,2,4-triazine##STR17## Step A: Preparation of3-Amino-5-(2-amino-1-ethylamino)-1,2,4-triazine, (16)

To a slurry of 3-amino-5-ethoxy-1,2,4-triazine (1.40 g, 0.0100 mol) inxylene (5 ml) was added ethylenediamine (1.00 ml, 0.0150 mol). Themixture was stirred at 120° C. for 3.5 hours, cooled, and concentratedto dryness in vacuo. The residue was stirred under ether, filtered off,and dried to give the title product, 16, (1.47 g, 95%, m.p. 186°-191°C.). TLC (20% methanol/chloroform/ammonia, silica): R_(f) =0.14.

Step B: Preparation of3-Amino-5-(2-{3-[(2-cyanophenoxy)-2-hydroxypropyl]amino}ethylamino)-1,2,4-triazine,(17)

To a solution of 3-(2-cyanophenoxy)propylene oxide (1.40 g, 0.0080 mol)in isopropanol (40 ml) was added a suspension of3-amino-5-(2-amino-1-ethylamino)-1,2,4-triazine (1.23 g, 0.0080 mol) inisopropanol (30 ml). The resulting solution was heated at 40° C. for 18hours. The warm mixture was then filtered and the insoluble material waswashed with isopropanol (20 ml). The combined filtrate was concentratedin vacuo to leave 2.40 g of solid which was chromatographed on a columnof silica gel 60 and eluted gradiently with 0-20% (v/v)methanol/chloroform followed by 20-50% methanol/chloroform saturatedwith ammonia. From the fraction eluted with 20% methanol/chloroformsaturated with ammonia there was obtained the crude product 17 (0.47 g,18%). The crude product was recrystallized from chloroform/ether to givethe purified product, 17, (0.22 g, 8%, m.p. 115°-120° C.).

Analysis satisfactory for C₁₅ H₁₉ N₇ O₂ : TLC (20% methanol/chloroform,silica): R_(f) =0.23.

EXAMPLE 112-[2-[[3-(2-Cyanophenoxy)-2-hydroxypropyl]amino]ethylaminopyrimidine,(18) ##STR18##

The amine 1 (1.52 g, 6.46 mmole) and 2-chloropyrimidine (740 mg, 6.46mmole) were heated at 60° C. in 2-propanol (5 ml) for 41/2 hours andthen stirred at room temperature overnight. The mixture was heated at60° C. for an additional 81/2 hours. The solvent was removed in vacuoand the product was purified by chromatography on silica gel 60 usingCH₂ Cl₂ -CH₃ OH-H₂ O (70-30-3 v:v:v) as the eluent to yield 870 mg (43%)of 18, m.p. 126°-128° C. Analysis satisfactory for C₁₆ H₁₉ N₅ O₂.1.5H₂O.

Following the procedures of the foregoing examples employing appropriatestarting materials, there are produced the following compounds.

    __________________________________________________________________________     ##STR19##                                                                    R.sup.1                                                                             R.sup.2     R.sup.3                                                                             n  Y                                                  __________________________________________________________________________    H     H           F     1                                                                                 ##STR20##                                         HO    H           H     2                                                                                 ##STR21##                                         HOCH.sub.2                                                                          H           H     3                                                                                 ##STR22##                                         H     HO          H     4                                                                                 ##STR23##                                         H     H           H.sub.2 N                                                                           5                                                                                 ##STR24##                                         H     (CH.sub.3).sub.2 N                                                                        H     6                                                                                 ##STR25##                                         H     CH.sub.3    CH.sub.3 NH                                                                         7                                                                                 ##STR26##                                         H     O.sub.2 N   C.sub.2 H.sub.5                                                                     8                                                                                 ##STR27##                                         H     CH.sub.3 O  CH.sub.3                                                                            1                                                                                 ##STR28##                                         H     H           C.sub.2 H.sub.5                                                                     2                                                                                 ##STR29##                                         H     n-C.sub.3 H.sub.7                                                                         H     2                                                                                 ##STR30##                                         H     H           n-C.sub.6 H.sub.13                                                                  2                                                                                 ##STR31##                                         H     c-C.sub.3 H.sub.5                                                                         CH.sub.3                                                                            2                                                                                 ##STR32##                                         H     H           c-C.sub.6 H.sub.11                                                                  2                                                                                 ##STR33##                                         H     CH.sub.3CHCH                                                                              H     2                                                                                 ##STR34##                                         H     H           CH.sub.3 O                                                                          2                                                                                 ##STR35##                                         H     (CH.sub.3).sub.2 CHO                                                                      H     1                                                                                 ##STR36##                                         H     H           C.sub.2 H.sub.5 S                                                                   2                                                                                 ##STR37##                                         H     CH.sub.3 CHCHO                                                                            H     3                                                                                 ##STR38##                                         H     H                                                                                          ##STR39##                                                                          4                                                                                 ##STR40##                                                ##STR41##  H     5                                                                                 ##STR42##                                         __________________________________________________________________________

    ______________________________________                                        INGREDIENT             AMOUNT (Mg.)                                           ______________________________________                                        TABLET FORMULATION I                                                          3-Methylamino-4[[2-[3-(2-cyano-                                                                       40.0                                                  phenoxy)-2-hydroxypropylamino]-                                               ethyl]amino]-1,2,5-thiadiazole-                                               1-oxide                                                                       calcium phosphate      120.0                                                  CAPSULE FORMULATION                                                           [[2-[[3-(2-Cyanophenoxy)-2-hydroxy-                                                                  250                                                    propyl]amino]ethyl]amino](methyl-                                             amino)methylene urea                                                          lactose, U.S.P.        93                                                     talc                    7                                                     INJECTABLE SOLUTION                                                           N--[Cyanoimino-[[2-[[3-(2-cyano-                                                                     5                                                      phenoxy)-2-hydroxypropyl]amino]-                                              ethyl]amino]]methylmorpholine                                                 sodium chloride        9                                                      distilled water, q.s.   1.0 ml.                                               LIQUID SUSPENSION                                                             N--2-[(3-(2-Cyanophenoxy)-2-hydroxy-                                                                 5.0                                                    propyl)amino]ethyl -N'--phenylthio-                                           urea 1.6 hydrate                                                              Veegum H.V.            3.0                                                    methyl paraben         1.0                                                    kaolin                 10.0                                                   glycerin               250.0                                                  water, q.s.            1 liter                                                ______________________________________                                    

What is claimed is:
 1. A compound having the structural formula: ##STR43## or a pharmaceutically acceptable salt thereof, wherein: Y is (1) ##STR44## wherein m is 1 or 2, n is 1-8;R¹ is(1) hydrogen, (2) hydroxy, or (3) hydroxymethyl; R² and R³ are independently:(1) hydrogen, (2) halo, (3) hydroxy, (4) amino, (5) di(C₁₋₅ alkyl)amino, (6) mono(C₁₋₅ alkyl)amino, (7) nitro, (8) cyano, (9) C₁₋₆ alkyl, (10) C₃₋₈ cycloalkyl, (11) C₂₋₅ alkenyl, (12) C₁₋₄ alkoxy, (13) C₁₋₄ alkylthio,(14) C₂₋₅ alkenyloxy, (15) C₁₋₅ alkanoyl; R⁴ and R⁵ are independently:(1) hydrogen, (2) C₁₋₆ alkyl, either unsubstituted or substituted with:(a) hydroxy, (b) C₁₋₄ alkoxy, or (3) ##STR45## wherein X is 0, 1 or 2; R⁴ and R⁵ are joined together to form a 5 membered ring with the nitrogen to which they are attached, R⁷ is(1) C₁₋₆ alkyl, (2) C₁₋₄ alkoxy, (3) or halo.
 2. The compound of claim 1 or a is pharmaceutically acceptable salt thereof wherein R¹ is hydrogen; R² and R³ are halo, nitro, C₁₋₅ alkanoyl, hydrogen or cyano; n is 2, and Y is: ##STR46##
 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof wherein R¹ and R² are hydrogen; and R³ is cyano.
 4. A pharmaceutical β-blocking composition comprising a pharmaceutically acceptable carrier and an effective β-blocking amount of a compound of formula: ##STR47## or a pharmaceutically acceptable salt thereof, wherein: Y is (1) ##STR48## wherein m is 1 or 2, n is 1-8;R¹ is(1) hydrogen, (2) hydroxy, or (3) hydroxymethyl; R² and R³ are independently:(1) hydrogen, (2) halo, (3) hydroxy, (4) amino, (5) di(C₁₋₅ alkyl)amino, (6) mono(C₁₋₅ alkyl)amino, (7) nitro, (8) cyano, (9) C₁₋₆ alkyl, (10) C₃₋₈ cycloalkyl, (11) C₂₋₅ alkenyl, (12) C₁₋₄ alkoxy, (13) C₁₋₄ alkylthio, (14) C₂₋₅ alkenyloxy, (15) C₁₋₅ alkanoyl; R⁴ and R⁵ are independently:(1) hydrogen, (2) C₁₋₆ alkyl, either unsubstituted or substituted with: (a) hydroxy, (b) C₁₋₄ alkoxy, or (c) phenyl; (3) ##STR49## wherein X is 0, 1 or 2; R⁴ and R⁵ are joined together to form a 5 membered ring with the nitrogen to which they are attached, R⁷ is(1) C₁₋₆ alkyl, (2) C₁₋₄ alkoxy, or (3) halo.
 5. The composition of claim 4 wherein R¹ is hydrogen, R² and R³ are halo, nitro, C₁₋₅ alkanoyl, hydrogen or cyano, n is 2, and Y is: ##STR50##
 6. The composition of claim 5, wherein R¹ and R² are hydrogen, and R³ is cyano.
 7. A method of treating hypertension, angina, arrhythmia, post myocardial infarction and/or elevated intraocular pressure in a patient in need of such treatment which comprises administration of an antihypertensive amount of a compound of structural formula: ##STR51## or a pharmaceutically acceptable salt thereof, wherein: Y is (1) ##STR52## wherein m is 1 or 2, n is 1-8R¹ is(1) hydrogen, (2) hydroxy, or (3) hydroxymethyl; R² and R³ are independently:(1) hydrogen, (2) halo, (3) hydroxy, (4) amino, (5) di(C₁₋₅ alkyl)amino, (6) mono(C₁₋₅ alkyl)amino, (7) nitro, (8) cyano, (9) C₁₋₆ alkyl, (10) C₃₋₈ cycloalkyl, (11) C₂₋₅ alkenyl, (12) C₁₋₄ alkoxy, (13) C₁₋₄ alkylthio, (14) C₂₋₅ alkenyloxy, (15) C₁₋₅ alkanoyl; R⁴ and R⁵ are independently:(1) hydrogen, (2) C₁₋₆ alkyl, either unsubstituted or substituted with:(a) hydroxy, (b) C₁₋₄ alkoxy, or (c) phenyl; (3) ##STR53## wherein X is 0, 1 or 2 R⁴ and R⁵ are joined together to form a 5 membered ring with the nitrogen to which they are attached, R⁶ is(1) --CN, (2) ##STR54## and R⁷ is (1) C₁₋₆ alkyl, (2) C₁₋₄ alkoxy or (3) halo.
 8. The method of claim 7 wherein R¹ is hydrogen R² ; and R³ are hydrogen, halo, nitro, C₁₋₅ -alkanoyl, or cyano; n is 2, and Y is: ##STR55##
 9. The method of claim 8 wherein R¹ and R² are hydrogen, and R³ is cyano.
 10. A compound according to claim 1 in which Y is ##STR56## wherein m is 1 or
 2. 11. A compound according to claim 10 in which R¹ is hydrogen; R² and R³ are independently hydrogen, halo, nitro, C₁₋₅ alkanoyl or cyano; n is 2; R⁴ is hydrogen or methyl, R⁵ is methyl, and m is
 1. 12. A compound according to claim 11 in which R¹ and R² are hydrogen, and R³ is cyano.
 13. A composition according to claim 4 wherein Y is ##STR57## wherein m is 1 or
 2. 14. A composition according to claim 13 wherein R¹ is hydrogen; R² and R³ are independently halo, nitro, C₁₋₅ alkanoyl, hydrogen or cyano; n is 2; R⁴ is hydrogen or methyl, R⁵ is methyl; and m is
 1. 15. A composition according to claim 13 wherein R¹ and R² are hydrogen, and R³ is cyano.
 16. A method according to claim 7 wherein Y is ##STR58## wherein m is 1 or
 2. 17. A method according to claim 16 wherein R¹ is hydrogen; R² and R³ are independently hydrogen, halo, nitro, C₁₋₅ alkanoyl or cyano; n is 2; R⁴ is hydrogen or methyl; R⁵ is methyl and m is
 1. 